2025 Patient Seminar Session: Clinical Trials at the National Cancer Institute (NCI), NIH

Pre-recorded Webinar Session Hosted by the Hairy Cell Leukemia Foundation with guest speaker Dr. Robert J. Kreitman from the National Cancer Institute (NCI), NIH.

View a recording of Dr. Robert Kreitman’s presentation below

Below, view transcripts of Dr. Kreitman’s presentation and Q&A.

Transcript of Dr. Kreitman’s Presentation

I would like to thank the Hairy Cell Leukemia Foundation for inviting me to speak on our National Cancer Institute (NCI), NIH clinical trial in classic and variant hairy cell leukemia. And I want to recognize the NIH for recognizing hairy cell leukemia as a rare disease.

What's the difference between hairy cell leukemia and hairy cell leukemia variant?

HCLv is a lower number of patients—less percentage—and there's more severe spleen enlargement and lymph nodes. The blood counts are more normal, but there's more leukemic cells in the blood. CD25 is negative, and the BRAF mutation is also not seen. Response to chemotherapy is poor.

And then in 2009, our lab described a new variant: IGHV4-34–positive hairy cell leukemia that's resembling hairy cell variant, as you can see. But it can be positive for CD25; if it is, they often call these patients hairy cell classic. If it's negative, they call them hairy cell variant. Either way, response to chemotherapy is very poor, and variant hairy cell tends to be more common among patients with relapsed or refractory hairy cell leukemia.

What does complete remission mean?

This is a term we're going to be using a lot here. It means that there's no hairy cell leukemia visible by standard stain—the H&E stain—of the bone marrow, where that goes away and is replaced by normal cells, as you can see on the right. But to get complete remission, you also have to have resolution of large spleen, lymph nodes, and high hairy cell counts, and you have to have your normal blood counts improve to these levels compared to the levels that you need to qualify for needing treatment.

That goes by the 1-10-100 rule, which has been in place for over 50 years. And there are other criteria you need treatment for if you don't have what they call symptoms, such as a painful spleen and growing lymph nodes.

Now, what about minimal residual disease (MRD)? We use this term an awful lot, and this can be seen by special stains of the bone marrow biopsy, flow cytometry of the blood and bone marrow, and the flow through the bone. Bone marrow aspirate is the most sensitive standard test, and molecular studies like PCR and next-generation sequencing are also very useful in detecting MRD. The importance of MRD is that complete remission can last longer if it's MRD-negative.

Now, hairy cell leukemia is not established to be curative, but we have patients who've been MRD-free for several decades. And for those patients, we think that they're cured. And if MRD is not negative, you can't say that the patient's cured.

These are the trials that we're actively following and treating patients on in the past five years. They target CD22, CD20, CD20 again, CD22 again, BRAF and MEK, and MEK only, BTK, BCL-2.

And we're going to talk about just the ones that are ongoing and accruing patients, which are the CAR T, the encorafenib/binimetinib for BRAF/MEK, binimetinib for MEK, and venetoclax. And a little bit about sorafenib/rituximab.

But the most common trial that our patients have is sending samples to NIH.

And you can do this if you don't even need to be treated, or if you don't want to be treated by our protocols. Patients with untreated or relapsed hairy cell leukemia or hairy cell variant often send samples to us to establish the diagnosis, rule out high-risk variants, determine the best treatment to start with, and sequence the hairy cells to be able to detect them after treatment in very low amounts to see if they're really MRD-free. And this is even more sensitive than flow cytometry of the bone marrow, but it's not standard. It's very important to contact us before patients get treated and before the treatment starts, and to delay treatment until the blood is drawn. It's fair to say that treatment of hairy cell leukemia and hairy cell variant is rarely urgent. Decisions should never be rushed about treatment. People should not rush into treatment—I've seen this many times. The first-line treatment is often cladribine, pentostatin, cladribine/rituximab, and there are newer regimens like vemurafenib/rituximab or vemurafenib/obinutuzumab.

Patients can send samples after treatment also to determine if they're MRD-free, to determine if they have MRD-free complete remission, and to determine if and when the next treatment might be needed, and if patients might be eligible for our protocols. Okay, let's start talking about the BRAF pathway.

We target the BRAF pathway with oral drugs. In hairy cell leukemia, BRAF, as you can see in green, if it carries the V600E mutation—shown in red—it overstimulates the pathway where you go from BRAF to MEK and then ERK, and that leads to cancer. If it happens in a B cell, it causes hairy cell leukemia. If it happens in a skin cell, it causes melanoma. And there are many other cancers where this pathway causes cancers. Vemurafenib inhibits V600E and resulted in 34–42% complete remissions in hairy cell leukemia, all MRD-positive. This is all work coming from Dr. Tiacci’s lab in Italy or his clinical service in Italy. Dabrafenib alone achieves 30% complete remissions, also all MRD-positive. In Italy, when they added rituximab to vemurafenib, they got not only a doubling of the complete remission, but also 57% of patients had MRD-free CR in relapsed hairy cell leukemia. In the U.S., dabrafenib/obinutuzumab achieved 90% complete remissions and 87% MRD-free complete remissions in untreated hairy cell leukemia. It's perhaps a little easier to get good responses in untreated hairy cell leukemia. Dabrafenib is another BRAF inhibitor—BRAF V600E—and trametinib inhibits MEK.

So, what is the advantage of treating with both a BRAF and a MEK inhibitor? We can see that using a BRAF inhibitor alone, in the middle here, blocks BRAF V600E down this red V600E pathway, but it increases the activity in normal BRAF; we call that wild-type BRAF. This can cause toxicities like squamous cell carcinoma, joint pains, fevers, skin lesions, pancreatitis. The MEK inhibitor—if you add a MEK inhibitor to a BRAF inhibitor, as you can see—blocks this overactivity of the wild-type pathway, the normal pathway, and it further blocks BRAF V600E. So, it's a win–win situation. Now, in melanoma, when you use dabrafenib/trametinib (BRAF inhibitor and MEK inhibitor), it was more effective and less toxic also than vemurafenib. So, we started a trial of dabrafenib and trametinib that we completed in 2020 and reported in 2023.

It was a multicenter trial of 55 patients, with a 66% complete remission rate. This was almost double vemurafenib, but it's apples to oranges because patients were on these drugs chronically; they didn't just get a short course like vemurafenib. Now, after two years, in fact, 94% of patients were still responding. Of 28 NIH patients on this trial of 55 patients—we treated 28 of them at NIH—15 (54%) remains in continuous complete remission at 7 to 11 years, 12 of whom still remain on treatment.

Now I'm going to talk about our trial that's enrolling patients now, and that's encorafenib/binimetinib. That's for relapsed BRAF V600E–mutated hairy cell leukemia, just like dabrafenib/trametinib.

The background of this trial is that in the COLUMBUS trial in melanoma, these agents that are FDA-approved for melanoma—encorafenib targeting BRAF and the MEK inhibitor binimetinib—were superior; they were better than dabrafenib/trametinib against melanoma and had less fever than dabrafenib/trametinib. To be eligible, patients have to have a mutation at V600, at least one prior purine analog. Of 28 patients whom we have so far evaluated, 94% have achieved complete remission, that's a very high complete remission rate. Twelve percent are MRD-free. So that complete remission rate is much higher than the MRD-free complete remission rate. Sixty-eight percent of our patients achieved complete remission by the earliest 12-week time point that we restage patients, and rituximab succeeded in converting MRD-positive to MRD-free complete remission in 3 out of 6 patients. We just started doing this, and more patients are now getting rituximab or obinutuzumab to convert MRD-positive to MRD-negative, or MRD-free complete remission. Another advance that we made with this trial is that fever was only seen in 11% with encorafenib/binimetinib, compared to 58.2% with dabrafenib/trametinib. This was another goal of the trial: to eliminate the fever, which can be really disabling in dabrafenib/trametinib. We don't see that with encorafenib/binimetinib.

Now, we are also treating with binimetinib alone in relapsed hairy cell leukemia and in hairy cell leukemia variant which does not have the V600E mutation. So, patients without a V600E mutation are not candidates for BRAF inhibitor therapy, and they often have aggressive disease and limited survival. To be eligible, they have to have hairy cell leukemia classic or variant without the BRAF V600E mutation and at least one purine analog. They're treated with binimetinib alone, it's an oral drug again. Patients in MRD-positive complete remission for a year can receive a CD20 antibody like rituximab or obinutuzumab to become MRD-free. Of eight patients, there have been two complete remissions so far, which are still ongoing after two to four years. This trial is more difficult to find patients for—not as many patients for this as classic hairy cell leukemia—and these patients don't do as well. So, to have two complete remissions is very good.

Now, what about venetoclax? This targets BCL-2, which is expressed by hairy cell leukemia and hairy cell leukemia variant. Dr. Tiacci reported that of six patients who relapsed after vemurafenib/rituximab, a third of them achieved MRD-positive CR with venetoclax, and Dr. Forconi also reported a patient treated with venetoclax who achieved a complete remission. So we are now leading a trial in the United States, supported by CTEP, for venetoclax in hairy cell leukemia and hairy cell leukemia variant. Either diagnosis is fine there, but it has to be relapsed after chemotherapy and BRAF inhibitor, or patients have to be ineligible for a BRAF inhibitor because of lack of the BRAF V600E mutation. That includes anyone with hairy cell leukemia variant, certainly. They have to need additional treatment and no treatment in the past four weeks. The protocol design is that patients begin on cycle one, day one. There are four-week cycles, and during the first cycle there's a slow increase in the venetoclax from 20 to 50 to 100 to 200 and 400 mg, so that the 400 mg per day begins on cycle two. Patients are seen before and at the beginning of cycles two and four and nine, and other times as needed. But you don't have to come back to NIH all the time for these visits—virtual visits are allowed. We check disease status by restaging at the beginning of cycle four and cycle nine. Treatment is complete at one and a half years. After that time, if you're doing well, you can get treated by your local doctor and we will still follow you, and even have you seen at NIH for the follow-up studies, as long as your local doctor is prescribing the venetoclax—and that's after a year and a half. Other sites include Ohio State, University of Miami, and many other sites in the United States.

So far, of four patients that we've evaluated as long as eight four-week cycles—this is like week 32—50% of them have already achieved complete remission, one of them MRD-free. There are no major toxicities. This is much better tolerated than BRAF inhibitors. Patients can get low neutrophil counts, but this improves with filgrastim (Neupogen), which we give to prevent problems. The first patient had pretty severe pancytopenia—you can see that the neutrophil count of 0.32, platelet count of 22—and this was associated with pneumonia. But this resolved after eight cycles, consistent with a complete remission. This patient is still on treatment to get better disease control. The second patient had hairy cell leukemia variant with prior cladribine, pentostatin, cladribine/bendamustine/rituximab, and relapsed with this large abdominal mass. This is shown in this CT—it was 7 by 4 centimeters. It was positive by PET with a high SUV of 11.5. After eight cycles, you can see here, this mass became insignificant in size and it was now negative by PET, consistent with an MRD-free complete remission. Bone marrow was also negative.

Now, this shows how we do CAR T therapy. CAR T is a very useful treatment these days for a lot of different leukemias and lymphomas and even other diseases. We take the blood, get the T cells out, and in the lab, we make CAR T cells by putting CD22 on the targeting antibodies so that it will bind to the hairy cells by binding to CD22. Hairy cell leukemia variant has loads of CD22 on them. We grow millions of CAR T cells in the lab, and then we infuse them back to the patient, and the CAR T cells go and find the cancer cells and kill them—in this case, hairy cells.

This shows who is eligible. Patients with hairy cell leukemia or hairy cell leukemia variant have to be relapsed after chemo and BRAF inhibitor, or be ineligible for BRAF inhibitor, or they could even just refuse BRAF inhibitor. But they have to need more treatment. They have to be CD22-positive, and all classic and variant hairy cell leukemias are strongly CD22-positive. They have to have no uncontrolled infection and good organ function. As I said, the first step is to do apheresis to collect the normal T cells, followed by the lab processing. Then they get chemotherapy—fludarabine and cyclophosphamide—to decrease normal T cells which might kill the CAR T cells as they go in. We then infuse the CAR T cells on day zero and follow the patient as an inpatient for at least 14 days until the toxicity period is over. The toxicity is mainly inflammation—we call that cytokine release syndrome (CRS)—and it's treated with different drugs that are highly effective.

This explains what happened to this patient. This is the fourth patient on our trial. On day minus six, which is six days before CAR T infusion, this posterior bladder mass that you can see right here on the PET scan was active with an SUV of 5.11 prior to CAR T infusion. A week after CAR T infusion, the hairy cells were detectable in the blood; they were gone a week later when the circulating CAR T cells first became detectable, and they were about half of all the T cells. One month after CAR T infusion, the CAR T cells were at 13%, and the posterior bladder mass, you can see, had already decreased down to 3.99—it looks more faint right here. On day +98, which is three months after CAR T infusion, there was a further decrease in the bladder mass down to 3.45, and there were liver abnormalities that suggested to us that the CAR T cells were going after the hairy cells in the liver, and they were causing some liver enzymes—not very high, but enough to notice that. On day 183, or six months after CAR T infusion, the bladder mass was finally negative by PET, consistent with a complete remission. Now, three months later, with the PET still negative, we did a transrectal biopsy of the posterior bladder mass, and that was negative by flow cytometry and immunohistochemistry; that was consistent with an MRD-free complete remission. One and a half years later, the PET and the bone marrow were still MRD-free. So, this was a very good response—not only because of the MRD-free complete remission, but it happened very gradually when the patient was home nearly the whole time. It was a very, very good result.

Now I want to end by talking about tovorafenib/rituximab for classic hairy cell leukemia, because tovorafenib is a class II (pan-RAF) BRAF inhibitor, which avoids some of the toxicities of the earlier class I BRAF inhibitors that we've already talked about, so that you don't need to add a MEK inhibitor to decrease toxicity. As you can see in this schema, in phase 1—the phase 1 part of the trial—there are 9 to 18 patients with relapsed hairy cell leukemia that get tovorafenib/rituximab. In phase 2, there are 66 patients with untreated hairy cell leukemia—as opposed to phase 1, where they're all relapsed. In phase 2, they're untreated hairy cell leukemias, and they'll be randomized 1:1 to receive either sorafenib/rituximab or cladribine/rituximab.

We and others have shown that cladribine/rituximab is an excellent regimen for hairy cell leukemia that gives very high MRD-free rates, in addition to a 100% complete remission rate. So, either way, this is a win–win situation for patients who agree to be randomized. This trial is now open at Ohio State with Dr. [team lead] and other CTEP sites, but it's opening in several months at NIH. This is a treatment plan where tovorafenib, shown in these red bars, is given weekly. The week numbers are shown in these numbers, which are black or white, and then white on black are the cycles. Cycles are four weeks long. The blue arrows are rituximab starting on cycle two, and then it's given weekly during cycle two and every other week during cycle three for a total of eight doses. With cladribine/rituximab, we also start rituximab on week five, and they get eight weekly doses of rituximab.

This summarizes all of our clinical trials: the sample collection protocol—the biggest one—where patients send samples after having blood drawn, or they can also come to NIH to have blood drawn. Anyone can do this. Encorafenib/binimetinib for patients with BRAF-positive classic hairy cell leukemia; binimetinib for HCL/HCLv that lacks V600E; CAR T which targets CD22 in HCL/HCLv; venetoclax in HCL/HCLv. And the future—hopefully coming soon—is tovorafenib/rituximab or cladribine/rituximab for relapsed and then untreated hairy cell leukemia. I want to recognize my teams, my clinical team and my lab team. I haven't seen them together in over a month now because of this terrible shutdown. I hope that ends soon. I also want to recognize Ira Pastan and David Fitzgerald, involved in immunotoxins, and also Ira has been involved in our CAR T trial, and especially for CAR T, Dr. N. Shah here at the Pediatric Oncology Branch of the NIH, who uses CAR T targeting CD22 for pediatric acute lymphoblastic leukemia.

Thank you very much, and I'm happy to answer questions.

Transcript of Q&A

This is a formatted summary of HCLF staff’s discussion with Dr. Robert Kreitman following his presentation.

Flexibility in Clinical Trial Participation

Question:
In the Venetoclax study, you mentioned that patients don’t have to travel to NIH for all follow-ups. Is that level of flexibility possible for patients participating in other trials?

Dr. Kreitman:
Yes. It’s really a feature of all our trials that patients don’t have to come for every visit. Some patients can even be restaged at home—though that can be complicated because insurance doesn’t always cover all the necessary tests. When there are many procedures, it’s often easier to do them at NIH.

For most visits, however, patients can see their local doctor or simply have labs drawn. We design our studies this way because most participants come from outside the area. Our goal is to make participation as convenient as possible.

Travel and Financial Support

Question:
For studies that require travel, are there funds available to help patients?

Dr. Kreitman:
Yes. We are working on travel funding, particularly for the CAR T trial, through a grant. For U.S. residents, NIH pays for all travel after the first trip. Patients cover the initial visit, although assistance is available for those in financial need.

Once enrolled, all travel expenses are covered. If patients stay in a hotel, they receive a stipend to help with costs. Staying at the NIH Clinical Center is completely free—NIH does not bill any insurance—and inpatient stays, such as during the CAR T program, are also free of charge.

For patients outside the United States, travel to the U.S. must be self-funded, but once they arrive, NIH covers the rest. For example, European patients who can reach New York are flown to NIH at no cost, and Canadian patients can travel to nearby U.S. airports like Buffalo and then fly free to NIH.

“NIH covers all travel expenses after the first trip, and all care at the NIH Clinical Center is completely free of charge.”
— Dr. Robert J. Kreitman

How to Contact the NIH Team

Question:
How can patients interested in these trials get in touch with your team?

Dr. Kreitman:
The best way is to email me directly—my address is on the HCLF website and on my slides presentation. I reply and cc our entire clinical team so the appropriate nurse can follow up. Lacey, our nurse practitioner, is always available, and the rest of the nursing team rotates during the week.

Usually, we begin by arranging for blood samples to be sent to us. If the patient lives nearby or wants to visit NIH, we can organize that very quickly—sometimes even faster than mailing the tubes. This helps us confirm eligibility and identify which protocol best fits each patient.

Sending Blood Samples

Question:
Do patients need active disease to send blood samples? And is that cost covered?

Dr. Kreitman:
No, patients do not need active disease. We often follow treated patients to monitor minimal residual disease (MRD). The only part billed to insurance is the CBC (complete blood count), which is standard and typically covered.

At the same time the patient gets their CBC and differential, they can fill our provided tubes. We send FedEx packages with prepaid labels—patients should not have to pay anything beyond their routine CBC.

Understanding CAR T-Cell Therapy

Question:
Does CAR T therapy include chemotherapy? Is it truly chemo-free?

Dr. Kreitman:
CAR T therapy involves a very low dose of chemotherapy called lymphodepleting chemotherapy. This is used to temporarily lower normal T-cell counts so the CAR T cells can function effectively once infused. We typically use fludarabine and cyclophosphamide—these are standard in most CAR T and transplant protocols.

Aside from that, the therapy is chemo-free and generally well tolerated.

Eligibility and Expectations for CAR T

Question:
Is CAR T therapy mainly for refractory patients, or could more patients benefit?

Dr. Kreitman:
It’s especially suitable for patients who have relapsed after BRAF inhibition—especially those who have also tried Venetoclax. The case I presented involved a patient with a very serious relapse but minimal toxicity during CAR T therapy. The patient stayed two weeks in the hospital, had an excellent response, and required no further treatment afterward.

We learned that reducing the number of hairy cells before CAR T—using a temporary treatment such as vemurafenib—helps minimize toxicity. We plan to treat 10–15 more patients and can expand enrollment if needed. Any patient who has exhausted other options should consider contacting us.

“Reducing the number of hairy cells before CAR T helps prevent toxicity and improves safety.”
— Dr. Robert J. Kreitman

Sequencing Treatments and Trial Eligibility

Question:
If a patient joins a clinical trial, can they later return to standard therapies like cladribine and rituximab?

Dr. Kreitman:
Yes. Participating in a trial does not limit future treatment options. All our current open trials are for relapsed hairy cell leukemia, including the sorafenib + rituximab study at Ohio State. Later, a phase 2 version will include newly diagnosed patients randomized against cladribine + rituximab.

The only caveat is that switching between similar BRAF inhibitors may reduce response—patients who receive one BRAF inhibitor, like encorafenib + binimetinib, may respond less to vemurafenib afterward. However, chemotherapy such as cladribine still works just as effectively regardless of prior targeted therapy.

Pan-BRAF Inhibitors and Reduced Toxicity

Comment:
Pan-BRAF inhibitors like Tovorafenib seem exciting, particularly for lowering skin-cancer risk.

Dr. Kreitman:
That’s correct. Class II or pan-BRAF inhibitors don’t activate feedback through the MAPK pathway, unlike class I inhibitors such as vemurafenib. This means fewer secondary skin cancers and inflammatory side effects—one of the main advantages of this new generation of drugs.

Advice for Patients Considering Clinical Trials

Question:
What message would you give to patients with relapsed hairy cell leukemia facing multiple treatment options?

Dr. Kreitman:
I strongly recommend seeking guidance from a hairy cell expert before starting any new therapy. The Hairy Cell Leukemia Foundation connects patients with experienced specialists. Sending your blood to NIH allows us to analyze your disease and provide expert input—free of charge—so you can make informed decisions.

Avoid rushing into treatment, especially for aggressive variants. Expert review helps match each patient’s medical history, prior therapies, and lab results to the best next step.

Closing Message from the Hairy Cell Leukemia Foundation

Patients are encouraged to seek consultation at a Center of Excellence or with an HCL specialist, especially before beginning treatment or at relapse. Expert evaluation of blood and bone-marrow samples can make a significant difference in outcomes.

We also remind our community that clinical trials are not experimental risks—they are opportunities. Every current standard therapy—from cladribine to BRAF inhibitors—exists because patients volunteered for earlier studies. When you join a clinical trial, you are cared for by expert teams and contribute to advancing treatments for every person living with hairy cell leukemia.

“You’re not a guinea pig—you’re part of a carefully monitored, expert-led effort to improve care for all patients.”

This transcript has been edited for clarity.